In 2004, 98,400 people in the U.S. were diagnosed with bladder cancer, 12,710 died of the disease. Within the US, Northern New England (including New Hampshire) has among the highest bladder cancer mortality rates. Epidemiologic studies that examined single SNPs and cancer susceptibility indicate modifying effects of certain genetic polymorphisms (e.g., NAT2). However, results for a number of polymorphisms are inconsistent. As yet no large-scale studies of bladder cancer have incorporated haplotype, gene-gene and gene-environment interactions in a comprehensive evaluation of variations in critical cancer control process genes. The completed parent population-based case-control study of bladder cancer incidence in New Hampshire has collected detailed exposure history and biologic specimens. Using a recently designed, cost-effective, genotyping panel for cancer, we propose to test approximately 542 cases and 585 controls for 1536 coding and haplotype tagging single nucleotide polymorphisms (SNPs) in approximately 250 cancer susceptibility genes. We will use both traditional logistic regression methods and newly developed methods for evaluating gene-gene and gene-environment interactions, i.e., Multifactor Dimensionality Reduction (MDR) and the Interaction Graph function in Orange Canvas. We will focus our initial analysis efforts on 48 genes in four important cancer regulatory pathways (the detoxification, cell cycle checkpoint, apoptosis, and inflammatory pathways). Analysis will be first be performed on inferred haplotypes and coding SNPs. We will then evaluate gene-gene and gene-environment interactions. Identifying the genetic and exposure factors that influence the risk of bladder cancer will provide critical information to reduce bladder cancer incidence and will facilitate chemoprevention efforts and the use of molecular diagnostic tools to design individualized treatment regimens. Relevance Of The Proposed Research To Public Health: This research project will use newly developed analysis tools to efficiently identify genetic risk factors for bladder cancer. We will also investigate the genetic basis for the inter-individual variation in risk following carcinogenic exposures including smoking. [unreadable] [unreadable] [unreadable]